The present invention relates to delivery devices, and methods, for delivering a bioactive agent to internal tissue in a body. The invention is particularly useful in delivering drugs of large molecular size and/or of fragile structure, such as protein drugs, and is therefore described below with respect to such an application, but it will be appreciated that the method could be used for the delivery of many other types of drugs, as well as other types of bioactive agents, such as herbal medications, homeopathic remedies, and traditional medications.
There is need for a drug delivery system that permits easy incorporation of a large variety of drugs without modification or alteration of the chemical structure and without affecting their activity. This is especially true for hydrophilic water soluble drugs such as proteins and peptides, heparins and oligo and polynucleotides (DNA or RNA) that are generally sensitive to deactivation by mechanisms including denaturation, aggregation, dimerization and chemical modification. The deactivation process may be induced by the use of organic solvents, the interface between water and the organic solvent, mechanical sheer applied, unfavor microenviroment around the active agent such as formation of acidic or basic local pH, high ionic strength and increase in drug concentration.
Protein drugs have been developed for treating hepatitis C, multiple sclerosis, hormonal disorders, and different cancers. However, the use of most protein drugs is limited by the inconvenient and invasive manner in which they must currently be administered. This involves either intravenous infusion or frequent subcutaneous or intramuscular injections throughout the therapy.
Delivering proteins is a challenge because of their large size and fragile three-dimensional structure, which must be maintained for biological activity. As a result, proteins exhibit poor oral bioavailability, eliminating the route by which small molecular weight drugs are most often delivered. A variety of approaches for improved delivery of therapeutic proteins are being explored in academia, government labs, and industry. injectable, biodegradable system that provides a sustained release of the agent over time is desired.
The development of effective systems for the sustained delivery of therapeutic proteins requires that several key obstacles are overcome. These include (i) processing and formulating the protein and delivery system so that the protein's fragile conformation and biological activity are maintained throughout processing and during prolonged release in the body, (ii) controlling the release so that therapeutic levels are maintained for the desired time, and (iii) developing a manufacturing process to produce quantities of sterile material for clinical trials and commercialization. In addition, it is desired that the delivery carrier will be degraded and eliminated from the body after the drug has been released.
A number of processes have been developed for the encapsulation of low molecular weight drugs in biodegradable microspheres by using phase separation, solvent evaporation, emulsion, or spray drying steps. However, the conditions typically used in these processes, such as elevated temperatures, high concentrations of surfactants, or organic and aqueous solvent mixtures, and apply of mechanical forces resulted in accelerated protein degradation. Degradation can decrease potency and increase immunogenicity, which in turn may adversely affect the safety and efficacy of the drug.
Maintaining stability of the protein following injection of a sustained release formulation poses a considerable challenge because proteins in microsphere formulations remain in a concentrated, hydrated state at physiological temperatures for prolonged periods after injection. These conditions are conducive to protein degradation reactions, including physical aggregation, deamidation, and oxidation. Several stabilization strategies can be used to maintain protein integrity under these conditions. The choice of one or more stabilizing agents is determined empirically. One effective approach is to form a complex with a divalent metal cation before encapsulation. Zinc has been employed in this manner to stabilize recombinant human growth hormone (rhGH) and recombinant a-interferon (a-IFN) in microspheres Also, protein stability in hydrated microspheres can be improved by using certain salts. For example, ammonium sulfate has been shown to stabilize erythropoietin during release.
In addition to maintaining protein stability during processing and release, the microsphere formulation must display the release kinetics required to achieve a sustained therapeutic effect. Following injection of the microspheres into the body, the encapsulated protein is released by a complex process involving hydration of the particles, dissolution of the drug, drug diffusion through water-filled pores within the particles, and polymer erosion. Two primary considerations are minimizing how much protein is released immediately (burst) and achieving the desired duration and rate of protein release. The duration of release is governed by the type of PLG polymer used and the addition of release modifying excipients such as zinc carbonate [Y. Zhang et al., J. Biomed. Mater. Res. 34, 531 (1997)]. The development of a sustained release system for a therapeutic protein begins with identifying a formulation with satisfactory stability characteristics and kinetics of release in animal models, toxicological and storage stability studies, and then human clinical testing.
Advantages inherent in sustained delivery of proteins are likely to include improved patient compliance (by reducing the need for self-injection), potentially lower costs (by reducing the frequency of visits to a caregiver's office), greater usage of a drug (through new indications and ease of use), and improved safety and efficacy (by reducing variability inherent in frequent injections). For certain proteins, it may also be possible to reduce the total dose per month, thereby reducing the cost to patients. Nevertheless, microsphere-based sustained delivery systems may be limited by the daily dose of protein needed for a therapeutic effect.
Biodegradable injectable in situ forming drug delivery systems represent an attractive alternative to microspheres and implants as parenteral depot systems. Their importance will grow as numerous proteins will lose their patent protection in the near future. These devices may offer attractive opportunities for protein delivery and could possibly extend the patent life of protein drugs. The controlled release of bioactive macromolecules via solid in situ forming systems has a number of advantages, such as ease of administration, less complicated fabrication, and less stressful manufacturing conditions for sensitive drug molecules. However, these systems still safer from non-desired release profile where significant amount of drug is released during the first few days with little in the days after. Also, a release for a few weeks can be achieved for certain short proteins and only days to 2-3 weeks for certain stable proteins. Sensitive proteins are exposed to acidic conditions in the polymer matrix during its degradation which deteriorate the incorporated therapeutic protein.
Alternative approaches for sustained delivery of therapeutic proteins are in various stages of development, there is no polymeric controlled delivery system in clinical use for proteins. There are two PLA based microsphere delivery systems for LHRH and somatostatin short peptides. One more microsphere delivery system was available for growth hormone that released the hormone for 2 weeks after injection.
Therapeutic proteins or peptides have short half-life of minutes in a human body and are easily denatured at the hydrophilic-hydrophobic interface. It is therefore very difficult to develop an efficient drug delivery system for extended release of the therapeutic proteins in vivo. For example, U.S. Pat. Nos. 6,586,011 6,616,944, and 5,019,400 discloses processes of preparing micropheres for delivering proteins by spraying lactide-glycolide based polymers into a freezing liquid. However, this process has a serious drawback of the deterioration in activity of protein drug due to the hydrophobicity of PLGA and organic solution. U.S. Pat. No. 6,616,944 discloses a process comprising steps of introducing to PLGA polymer a functional group capable of forming an ionic bond with a protein and loading a protein drug to provide a protein drug-nanoparticle composite. However, this process causes polymer degradation and protein deterioration. Hydrogel based protein delivery systems have also been developed but show high initial burst of the drug instability over time and uncontrolled biodegradability.
An implantable osmotic pump system reportedly delivers peptide drugs at a constant rate for up to 1 year [J. C. Wright, et al., Proc. Int. Symp. Controlled Release Bioact. Mater. 24, 59 (1997)]. This pump can be loaded with an aqueous solution of a stabilized protein which is constantly released through an orifice for a predetermine time period. Similar reservoir implantable delivery systems for peptides and proteins have been reported during the past three decades. In one system, LHRH analogs have been loaded in a sealed non-degradable HEMA hydrogel cylinder where LHRH was constantly released for over one year both in vitro and in vivo.
While these reservoir systems showed to be most effective in releasing the protein for months at a zero order kinetics will no degradation of the loaded protein, these systems did not find broad clinical applications due to the need for a surgical procedure for implanting the device and the need to retrieve the device after depletion of the loaded drug.